Project Summary/Abstract: Our overall foundation is that there are identifiable genetic predispositions to the development of pancreatic cancer. Our prior work has established the importance of inherited factors in the development of pancreatic cancer, and identified BRCA2, PALB2 and ATM as familial pancreatic cancer genes. However, the familial clustering is still unexplained for 80% of pancreatic cancer families. This leads to our overall translational goals; to increase our scientific evidence base to inform genetic counseling and risk assessment of at-risk individuals by identifying new pancreatic cancer genes and to identify people at high-risk who would benefit most from future chemoprevention trials and efforts to screen for early, and therefore potentially curable, pancreatic neoplasia. As part of this project we will 1A) To determine the contribution of germline structural variants to pancreatic cancer susceptibility; 1B) To identify novel pancreatic cancer susceptibility genes through a combined analysis of single nucleotide variants and structural variants: 2) To evaluate and characterize candidate pancreatic cancer susceptibility genes; 3A) To determine if personal or family histories of cancers other than pancreatic cancer can be used to better estimate the risk of developing pancreatic cancer 3B) to develop and validate an enhanced and clinically practical pancreatic cancer risk stratification model incorporating risk factors identified in Aims 1, 2 and 3A. In summary, through this project we hope to continue to unravel the genetic basis of inherited pancreatic cancer and develop practical, robust and clinically relevant tools to guide precision risk-management strategies for these families.